The transfusion-related respiratory complications transfusion-related acute lung injury (TRALI) and transfusion- associated circulatory overload (TACO) are leading causes of transfusion-related death. At present, there are no effective strategies for the prevention of these complications following red blood cell (RBC) transfusion. Although the mechanisms that underlie these complications remain incompletely defined, soluble biological response modifiers (BRMs) residing within the RBC storage solution are believed to play an important role. Point-of-care washing of allogeneic RBCs prior to transfusion may remove these BRMs, thereby mitigating their impact on postoperative respiratory complications. Our long-range goals are to develop effective strategies that can prevent TRALI and TACO. The objective of this proposal is to evaluate the feasibility, safety, efficacy, and clinical impact of point-of-care washing for allogeneic leukocyte-reduced (LR) RBCs using an FDA-approved autotransfusion system. We will specifically evaluate the impact of this intervention on intermediate markers of transfusion-related respiratory complications in patients undergoing high-risk cardiac surgery. We further aim to better understand the mechanisms underlying these complications. To achieve these objectives, this application proposes the following specific aims. AIM 1: To determine the feasibility, safety, and efficacy of point-of-care RBC washing using the Continuous AutoTransfusion System (CATS) device in adult cardiac surgery patients receiving allogeneic LR-RBC transfusion. AIM 2: To demonstrate the extent to which point-of-care washing of allogeneic LR-RBCs impacts the recipient response to RBC transfusion when compared to standard-issue allogeneic LR-RBCs. AIM 3: To evaluate the impact of point-of-care washing of allogeneic LR-RBCs on recipient's clinical outcomes. To accomplish these aims, we proposed a multicenter phase I/II randomized clinical trial. Adult cardiac surgery patients receiving allogeneic LR-RBC transfusion will be randomized to receive either point-of-care, washed RBCs using the CATS device or standard-issue RBCs on the day of surgery. A validated risk prediction model will be used to facilitate targeted enrollment into this trial. This proposal addresses multiple highlighted topics in this funding opportunity announcement, including but not limited to: 1) non-infectious complications of blood transfusion including TRALI; 2) immunomodulatory, inflammatory and vasoregulatory properties of transfused blood components; and 3) evaluation of the impact of introducing a new blood product preparation or transfusion strategies on transfusion-associated adverse events and recipients' clinical outcomes.